tbuckley/cabot-search huggingface dataset:
Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2–Associated Sepsis
Authors: Claire N. Shappell, Michael Klompas, Christina Chan, Tom Chen, Sanjat Kanjilal, Caroline McKenna, Chanu Rhee
Journal: JAMA Network Open (2023)

Importance Efforts to quantify the burden of SARS-CoV-2–associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. Objective To describe the incidence and outcomes of SARS-CoV-2–associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. Design, Setting, and Participants This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. Exposures SARS-CoV-2–associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2–associated sepsis). Main Outcomes and Measures Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2–associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. Results This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2–associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2–associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2–positive hospitalizations confirmed electronic health record (EHR)–based SARS-CoV-2–associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). Conclusions and Relevance In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2–associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2–associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.
Reducing Child Poverty—What Money Can Buy
Authors: Benard P. Dreyer
Journal: JAMA Network Open (2023)

Jessica F. Sperber, BA; Lisa A. Gennetian, PhD; Emma R. Hart, BS; Alicia Kunin-Batson, PhD; Katherine Magnuson, PhD; Greg J. Duncan, PhD; Hirokazu Yoshikawa, PhD; Nathan A. Fox, PhD; Sarah Halpern-Meekin, PhD; Kimberly G. Noble, MD, PhD
Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites
Authors: Nikhat Shaikh, Alex Waterhölter, Ann-Christin Gnirck, Martina Becker, Virginia Adamiak, Lena Henneken, Malte Wunderlich, Wiebke Hartmann, Lara Linnemann, Tobias B. Huber, Christian F. Krebs, Ulf Panzer, Richard M. Locksley, Christoph Wilhelm, Minka Breloer, Jan-Eric Turner
Journal: The Journal of Experimental Medicine (2023)

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.
Real-world evaluation of UK high hyperdiploidy profile using a large cohort of patients provided by HARMONY data platform
Authors: Amir Enshaei, Javier Martinez Elicegui, Esther Anguiano, Jude Gibson, Sulaiman Lawal, Mirella Ampatzidou, Michael Doubek, Adele K. Fielding, Edoardo La Sala, Elizabeth Middleton, Anita W. Rijneveld, Amin T. Turki, Martin Zimmermann, Ajay Vora, Anthony V. Moorman
Journal: Leukemia (2023)
A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial–temporal regulation of histone arginine methylation in neurodevelopment
Authors: Xiaolin Lin, Wei Wang, Mingyi Yang, Nadirah Damseh, Mirta Mittelstedt Leal de Sousa, Fadi Jacob, Anna Lång, Elise Kristiansen, Marco Pannone, Miroslava Kissova, Runar Almaas, Anna Kuśnierczyk, Richard Siller, Maher Shahrour, Motee Al-Ashhab, Bassam Abu-Libdeh, Wannan Tang, Geir Slupphaug, Orly Elpeleg, Stig Ove Bøe, Lars Eide, Gareth J. Sullivan, Johanne Egge Rinholm, Hongjun Song, Guo-li Ming, Barbara van Loon, Simon Edvardson, Jing Ye, Magnar Bjørås
Journal: Genome biology (2023)

Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency.We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial-temporal regulation of histone arginine methylation in specific brain regions.This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.
<i>ERJ</i>Podcast September 2023: ERS International Congress 2023
Journal: European Respiratory Journal (2023)

As part of the September issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief Editor James Chalmers, Deputy Chief Editor Don Sin, and Section Editors Isabella Annesi-Maesano and Joan Soriano talk about the Best of the ERJ session at the ERS International Congress 2023 and their favourite sessions from the rest of the Congress.
Naturalistic reinforcement learning
Authors: Toby Wise, Kara Emery, Angela Radulescu
Journal: Trends in Cognitive Sciences (2023)

Humans possess a remarkable ability to make decisions within real-world environments that are expansive, complex, and multidimensional. Human cognitive computational neuroscience has sought to exploit reinforcement learning (RL) as a framework within which to explain human decision-making, often focusing on constrained, artificial experimental tasks. In this article, we review recent efforts that use naturalistic approaches to determine how humans make decisions in complex environments that better approximate the real world, providing a clearer picture of how humans navigate the challenges posed by real-world decisions. These studies purposely embed elements of naturalistic complexity within experimental paradigms, rather than focusing on simplification, generating insights into the processes that likely underpin humans' ability to navigate complex, multidimensional real-world environments so successfully.
Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing
Authors: Leilei Cui, Bin Yang, Shijun Xiao, Jun Gao, Amelie Baud, Delyth Graham, Martin McBride, Anna Dominiczak, Sebastian Schafer, Regina Lopez Aumatell, Carme Mont, Albert Fernandez Teruel, Norbert Hübner, Jonathan Flint, Richard Mott, Lusheng Huang
Journal: Genome biology (2023)

Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively.We systematically investigate both dominance-here representing any non-additive within-locus interaction-and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance.Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.
Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function
Authors: Qian Zhang, Johnvesly Basappa, Hong Y. Wang, Selene Nunez-Cruz, Cosimo Lobello, Shengchun Wang, Xiaobin Liu, Seble Chekol, Lili Guo, Amy Ziober, Reza Nejati, Alex Shestov, Michael Feldman, Jerry D. Glickson, Suzanne D. Turner, Ian A. Blair, Chi Van Dang, Mariusz A. Wasik
Journal: Leukemia (2023)
Antitumor activity of the investigational B7-H3 antibody-drug conjugate, vobramitamab duocarmazine, in preclinical models of neuroblastoma
Authors: Chiara Brignole, Enzo Calarco, Veronica Bensa, Elena Giusto, Patrizia Perri, Eleonora Ciampi, Maria Valeria Corrias, Simonetta Astigiano, Michele Cilli, Derik Loo, Ezio Bonvini, Fabio Pastorino, Mirco Ponzoni
Journal: Journal for ImmunoTherapy of Cancer (2023)

Introduction B7-H3 is a potential target for pediatric cancers, including neuroblastoma (NB). Vobramitamab duocarmazine (also referred to as MGC018 and herein referred to as vobra duo) is an investigational duocarmycin-based antibody-drug conjugate (ADC) directed against the B7-H3 antigen. It is composed of an anti-B7-H3 humanized IgG1/kappa monoclonal antibody chemically conjugated through a cleavable valine-citrulline linker to a du ocarmycin-hydroxy b enzamide a zaindole (vc-seco-DUBA). Vobra duo has shown preliminary clinical activity in B7-H3-expressing tumors. Methods B7-H3 expression was evaluated by flow-cytometry in a panel of human NB cell lines. Cytotoxicity was evaluated in monolayer and in multicellular tumor spheroid (MCTS) models by the water-soluble tetrazolium salt,MTS, proliferation assay and Cell Titer Glo 3D cell viability assay, respectively. Apoptotic cell death was investigated by annexin V staining. Orthotopic, pseudometastatic, and resected mouse NB models were developed to mimic disease conditions related to primary tumor growth, metastases, and circulating tumor cells with minimal residual disease, respectively. Results All human NB cell lines expressed cell surface B7-H3 in a unimodal fashion. Vobra duo was cytotoxic in a dose-dependent and time-dependent manner against all cell lines (IC50 range 5.1–53.9 ng/mL) and NB MCTS (IC50 range 17.8–364 ng/mL). Vobra duo was inactive against a murine NB cell line (NX-S2) that did not express human B7-H3; however, NX-S2 cells were killed in the presence of vobra duo when co-cultured with human B7-H3-expressing cells, demonstrating bystander activity. In orthotopic and pseudometastatic mouse models, weekly intravenous treatments with 1 mg/kg vobra duo for 3 weeks delayed tumor growth compared with animals treated with an irrelevant (anti-CD20) duocarmycin-ADC. Vobra duo treatment for 4 weeks further increased survival in both orthotopic and resected NB models. Vobra duo compared favorably to TOpotecan-TEMozolomide (TOTEM), the standard-of-care therapy for NB relapsed disease, with tumor relapse delayed or arrested by two or three repeated 4-week vobra duo treatments, respectively. Further increased survival was observed in mice treated with vobra duo in combination with TOTEM. Vobra duo treatment was not associated with body weight loss, hematological toxicity, or clinical chemistry abnormalities. Conclusion Vobra duo exerts relevant antitumor activity in preclinical B7-H3-expressing NB models and represents a potential candidate for clinical translation.
Coronary Computed Tomographic Angiography With Fractional Flow Reserve in Patients With Type 2 Myocardial Infarction
Authors: Cian P. McCarthy, Sean P. Murphy, Daniel K. Amponsah, Paula K. Rambarat, Claire Lin, Yuxi Liu, Reza Mohebi, Allison Levin, Avanthi Raghavan, Hannah Miksenas, Campbell Rogers, Jason H. Wasfy, Ron Blankstein, Brian Ghoshhajra, Sandeep Hedgire, James L. Januzzi
Journal: Journal of the American College of Cardiology (2023)
Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection
Authors: Luisella Spiga, Ryan T. Fansler, Yasiru R. Perera, Nicolas G. Shealy, Matthew J. Munneke, Holly E. David, Teresa P. Torres, Andrew Lemoff, Xinchun Ran, Katrina L. Richardson, Nicholas Pudlo, Eric C. Martens, Ewa Folta-Stogniew, Zhongyue J. Yang, Eric P. Skaar, Mariana X. Byndloss, Walter J. Chazin, Wenhan Zhu
Journal: Cell Host & Microbe (2023)
Select symbionts drive high IgA levels in the mouse intestine
Authors: Shanshan Zhang, Yi Han, Whitman Schofield, Michael Nicosia, Paul E. Karell, Kevin P. Newhall, Julie Y. Zhou, Ryan J. Musich, Siyi Pan, Anna Valujskikh, Naseer Sangwan, Mohammed Dwidar, Qiuhe Lu, Thaddeus S. Stappenbeck
Journal: Cell Host & Microbe (2023)
Characterizing intergenic transcription at RNA polymerase II binding sites in normal and cancer tissues
Authors: Pierre de Langen, Fayrouz Hammal, Elise Guéret, Jean-Christophe Mouren, Lionel Spinelli, Benoit Ballester
Journal: Cell Genomics (2023)

Intergenic transcription in normal and cancerous tissues is pervasive but incompletely understood. To investigate this, we constructed an atlas of over 180,000 consensus RNA polymerase II (RNAPII)-bound intergenic regions from 900 RNAPII chromatin immunoprecipitation sequencing (ChIP-seq) experiments in normal and cancer samples. Through unsupervised analysis, we identified 51 RNAPII consensus clusters, many of which mapped to specific biotypes and revealed tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAPII atlas with active transcription across 28,797 RNA sequencing (RNA-seq) samples from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Encyclopedia of DNA Elements (ENCODE). This analysis revealed strong tissue- and disease-specific interconnections between RNAPII occupancy and transcriptional activity. We demonstrate that intergenic transcription at RNAPII-bound regions is a novel per-cancer and pan-cancer biomarker. This biomarker displays genomic and clinically relevant characteristics, distinguishing cancer subtypes and linking to overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover intergenic transcriptional activity in normal and cancer tissues.
Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial
Authors: Nobuaki Matsubara, Ronald de Wit, Arjun Vasant Balar, Arlene O. Siefker-Radtke, Jakub Zolnierek, Tibor Csoszi, Sang Joon Shin, Se Hoon Park, Vagif Atduev, Mahmut Gumus, Yu-Li Su, Saziye Burcak Karaca, Hernán Javier Cutuli, Mehmet A.N. Sendur, Liji Shen, Karen O'Hara, Chinyere E. Okpara, Sonia Franco, Blanca Homet Moreno, Petros Grivas, Yohann Loriot
Journal: European Urology (2023)
Proteomic approaches advancing targeted protein degradation
Authors: Gajanan Sathe, Gopal P. Sapkota
Journal: Trends in Pharmacological Sciences (2023)

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.
Physical fitness among children with diverse weight status during and after the COVID-19 pandemic: a population-wide, cohort study based on the Slovenian physical fitness surveillance system (SLOfit)
Authors: Antonio Martinko, Maroje Sorić, Gregor Jurak, Gregor Starc
Journal: The Lancet Regional Health - Europe (2023)

COVID-19 public health crisis has exerted immediate negative impacts on children's physical fitness, but the longer-term effects are not clear, and the impact on children with excess weight is yet unknown. We examined changes in multiple components of physical fitness in response to COVID-19 imposed restrictions, but also a year after the restrictions were terminated, and compared these trends in groups of boys and girls with normal weight, overweight, or obesity before the pandemic.Information was gathered through Slovenia's national fitness surveillance system, and included 41,330 children (19,890 girls), aged 5-17, who had their fitness levels measured yearly from 2019 to 2022. Multilevel linear mixed models, fitted separately for boys and girls, were used to model the individual-level trends over time in centile score for each fitness test across 3 weight groups.Overall fitness levels decreased markedly across all weight categories between 2019 and 2020, with the largest decreases in Total Fitness Index observed in children with normal weight and overweight (-8.4 and -7.7 centiles for boys and -8.3 and -8.8 for girls, respectively, p < 0.001). While there was some recovery in the overall fitness level between 2020 and 2022, it remained much lower in 2022 compared to 2019 across most groups, apart from boys with obesity. Fitness components that had the largest impact on general fitness trends were cardiorespiratory fitness, lower body power, body core, and upper body strength.A severe decline in fitness that has not come close to returning to pre-pandemic levels in most population groups of youth begs for urgent population-wide initiatives that will provide additional opportunities for physical activity to youth. Among vulnerable groups, girls with overweight and obesity deserve a special focus of these policies.Horizon 2020 (Grant no. 774548), Slovenian National Research Agency (Grant no. P5-0142), Croatian Science Foundation (Grant no. DOK-2020-01-3728).
Magnetic nanoparticles for ferroptosis cancer therapy with diagnostic imaging
Authors: Min Jun Ko, Sunhong Min, Hyunsik Hong, Woojung Yoo, Jinmyoung Joo, Yu Shrike Zhang, Heemin Kang, Dong-Hyun Kim
Journal: Bioactive Materials (2023)

Ferroptosis offers a novel method for overcoming therapeutic resistance of cancers to conventional cancer treatment regimens. Its effective use as a cancer therapy requires a precisely targeted approach, which can be facilitated by using nanoparticles and nanomedicine, and their use to enhance ferroptosis is indeed a growing area of research. While a few review papers have been published on iron-dependent mechanism and inducers of ferroptosis cancer therapy that partly covers ferroptosis nanoparticles, there is a need for a comprehensive review focusing on the design of magnetic nanoparticles that can typically supply iron ions to promote ferroptosis and simultaneously enable targeted ferroptosis cancer nanomedicine. Furthermore, magnetic nanoparticles can locally induce ferroptosis and combinational ferroptosis with diagnostic magnetic resonance imaging (MRI). The use of remotely controllable magnetic nanocarriers can offer highly effective localized image-guided ferroptosis cancer nanomedicine. Here, recent developments in magnetically manipulable nanocarriers for ferroptosis cancer nanomedicine with medical imaging are summarized. This review also highlights the advantages of current state-of-the-art image-guided ferroptosis cancer nanomedicine. Finally, image guided combinational ferroptosis cancer therapy with conventional apoptosis-based therapy that enables synergistic tumor therapy is discussed for clinical translations.